PROGRAM SUMMARY/ABSTRACT Immune regulation plays a critical role in tolerance and tumor surveillance. Insight into these mechanisms have arisen from studies on patients and animal models with mutations in FOXP3 for IPEX syndrome or AIRE for APS-1 syndrome. Understanding these mechanisms have led to novel therapies. Dr. Alice Chan?s career focus is to understand perturbations in immune regulation by studying animal models and patients, with the goal of translating the biology into clinical practice to improve patient care. Her interest in immune dysregulation started from her research work during her MD/PhD training. She then became board-certified in both Pediatric Rheumatology and Allergy/Immunology to care for patients with immune dysregulation disorders in a clinic she established for this unique patient cohort. Studies on these patients have led to several publications, including a first author paper. To continue her career development, she has proposed a 5-year career development plan to transition her to become a physician scientist with an independent research program. The plan cultivates both professional and scientific skills as well as an independent research portfolio. She will have direct mentorship by Dr. Mark Anderson and her advisory committee, which includes a carefully curated group of well-recognized scientists and physicians with expertise in T cell biology and clinical immunology. Her proposed coursework, conferences and workshops will help her achieve new technical expertise and refine professional skills. Her research proposal focuses on unraveling the molecular mechanisms behind a novel gene, Mosaic, which has been identified as the causal gene for a multiorgan system autoimmunity in a subset of canines. Given that Mosaic is a highly conversed protein among vertebrates, Dr. Chan has developed several Mosaic mouse models with preliminary data supporting a role in T cell function. The research proposal has 3 aims: Aim 1 defines the mechanism(s) by which Mosaic maintains peripheral T cell homeostasis. Aim 2 defines the molecular pathway(s) through which Mosaic modifies Th17 effector function. Aim 3 determines the ability of defects in Mosaic to drive autoimmunity. The proposed aims will not only develop scientific skills but also build a research portfolio to establish herself as an independent investigator. Her training will be at UCSF which is an ideal environment that supports physician scientists. The Department of Pediatrics has a long track record of fostering the career development of young faculty. The UCSF immunology community includes a broad collection of investigators who are leaders in a wide breadth of research arenas that will accelerate Dr. Chan?s personal and professional growth. In summary at the completion of this career development award, Dr. Chan will have cultivated the necessary skills to launch her own independent research program. This proposal builds on her long-standing research and clinical interest in immune dysregulation and will foster her success as a physician scientist.